Interactions of Aromatic Radicals with Water

The interactions of the benzyl radical (1), the anilinyl radical (2), and the phenoxyl radical (3) with water are investigated using density functional theory (DFT). In addition, we report dispersion-corrected DFT-D molecular dynamics simulations on these three systems and a matrix isolation study on 1–water. The radicals 1–3 form an interesting series with the number of lone pairs increasing from none to two. The anilinyl and benzyl radicals can act as Lewis base through their unpaired electrons, the lone pairs of the heteroatoms, or the doubly occupied π orbitals of the aromatic system. Matrix isolation experiments provide evidence for the formation of a π complex between 1 and water. By combining computational and experimental techniques we identify the possible interactions between the aromatic radicals 1–3 and water, predict the structure and vibrational spectra of the resulting complexes, and analyze the effects of substitution and temperature

A 3-mode, Variable Velocity Jet Model for HH 34

Variable ejection velocity jet models can qualitatively explain the appearance of successive working surfaces in Herbig-Haro (HH) jets. This paper presents an attempt to explore which features of the HH-34 jet can indeed be reproduced by such a model. From previously published data on this object, we find evidence for the existence of a 3-mode ejection velocity variability, and then explore the implications of such a variability. From simple, analytic considerations it is possible to show that the longer period modes produce a modulation on the shorter period modes, resulting in the formation of ``trains'' of multiple knots. The knots observed close to the source of HH-34 could correspond to such a structure. Finally, a numerical simulation with the ejection velocity variability deduced from the HH-34 data is computed. This numerical simulation shows a quite remarkable resemblance with the observed properties of the HH-34 jet.Comment: 28 pages LaTex, 10 postscript figure

Global and regional cortical thinning in first-episode psychosis patients: relationships with clinical and cognitive features

BackgroundThe thickness of the cortical mantle is a sensitive measure for identifying alterations in cortical structure. We aimed to explore whether first episode schizophrenia patients already show a significant cortical thinning and whether cortical thickness anomalies may significantly influence clinical and cognitive features.MethodWe investigated regional changes in cortical thickness in a large and heterogeneous sample of schizophrenia spectrum patients (n=142) at their first break of the illness and healthy controls (n=83). Magnetic resonance imaging brain scans (1.5 T) were obtained and images were analyzed by using BRAINS2. The contribution of sociodemographic, cognitive and clinical characterictics was investigated.ResultsPatients showed a significant total cortical thinning (F=17.55, d=−0.62, p0.53). No significant group × gender interactions were observed (all p’s>0.15). There were no significant associations between the clinical and pre-morbid variables and cortical thickness measurements (all r’s<0.12). A weak significant negative correlation between attention and total (r=−0.24, p=0.021) and parietal cortical thickness (r=−0.27, p=0.009) was found in patients (thicker cortex was associated with lower attention). Our data revealed a similar pattern of cortical thickness changes related to age in patients and controls.ConclusionsCortical thinning is independent of gender, age, age of onset and duration of the illness and does not seem to significantly influence clinical and functional symptomatology. These findings support a primary neuro-development disorder affecting the normal cerebral cortex development in schizophrenia

Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM 9906 trial

INTRODUCTION: EndoPredict (EP) is an RNA-based multigene test that predicts the likelihood of distant recurrence in patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2–negative (HER2−) breast cancer (BC) who are being treated with adjuvant endocrine therapy. Herein we report the prospective-retrospective clinical validation of EP in the node-positive, chemotherapy-treated, ER+/HER2− BC patients in the GEICAM 9906 trial. METHODS: The patients (N = 1,246) were treated either with six cycles of fluorouracil, epirubicin and cyclophosphamide (FEC) or with four cycles of FEC followed by eight weekly courses of paclitaxel (FEC-P), as well as with endocrine therapy if they had hormone receptor–positive disease. The patients were assigned to EP risk categories (low or high) according to prespecified cutoff levels. The primary endpoint in the clinical validation of EP was distant metastasis-free survival (MFS). Metastasis rates were estimated using the Kaplan-Meier method, and multivariate analysis was performed using Cox regression. RESULTS: The molecular EP score and the combined molecular and clinical EPclin score were successfully determined in 555 ER+/HER2− tumors from the 800 available samples in the GEICAM 9906 trial. On the basis of the EP, 25% of patients (n = 141) were classified as low risk. MFS was 93% in the low-risk group and 70% in the high-risk group (absolute risk reduction = 23%, hazard ratio (HR) = 4.8, 95% confidence interval (CI) = 2.5 to 9.5; P < 0.0001). Multivariate analysis showed that, in this ER+/HER2− cohort, EP results are an independent prognostic parameter after adjustment for age, grade, lymph node status, tumor size, treatment arm, ER and progesterone receptor (PR) status and proliferation index (Ki67). Using the predefined EPclin score, 13% of patients (n = 74) were assigned to the low-risk group, who had excellent outcomes and no distant recurrence events (absolute risk reduction vs high-risk group = 28%; P < 0.0001). Furthermore, EP was prognostic in premenopausal patients (HR = 6.7, 95% CI = 2.4 to 18.3; P = 0.0002) and postmenopausal patients (HR = 3.3, 95% CI = 1.3 to 8.5; P = 0.0109). There were no statistically significant differences in MFS between treatment arms (FEC vs FEC-P) in either the high- or low-risk groups. The interaction test results between the chemotherapy arm and the EP score were not significant. CONCLUSIONS: EP is an independent prognostic parameter in node-positive, ER+/HER2− BC patients treated with adjuvant chemotherapy followed by hormone therapy. EP did not predict a greater efficacy of FEC-P compared to FEC alone

Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens

Altres ajuts: This work was carried out at the Esther Koplowitz Center, Barcelona. Genmab and Janssen pharmaceuticals funded this research. Additional grants that contributed to this work included: [...], and CIBERONC (CB16/12/00334 and CB16/12/00225).CD38 is expressed in several types of non-Hodgkin lymphoma (NHL) and constitutes a promising target for antibody-based therapy. Daratumumab (Darzalex) is a first-in-class anti-CD38 antibody approved for the treatment of relapsed/refractory (R/R) multiple myeloma (MM). It has also demonstrated clinical activity in Waldenström macroglobulinaemia and amyloidosis. Here, we have evaluated the activity and mechanism of action of daratumumab in preclinical in vitro and in vivo models of mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), as monotherapy or in combination with standard chemo-immunotherapy. In vitro, daratumumab engages Fc-mediated cytotoxicity by antibody-dependent cell cytotoxicity and antibody-dependent cell phagocytosis in all lymphoma subtypes. In the presence of human serum, complement-dependent cell cytotoxicity was marginally engaged. We demonstrated by Selective Plane Illumination Microscopy that daratumumab fully penetrated a three-dimensional (3D) lymphoma organoid and decreased organoid volume. In vivo, daratumumab completely prevents tumor outgrowth in models of MCL and FL, and shows comparable activity to rituximab in a disseminated in vivo model of blastic MCL. Moreover, daratumumab improves overall survival (OS) in a mouse model of transformed CD20 FL, where rituximab showed limited activity. Daratumumab potentiates the antitumor activity of CHOP and R-CHOP in MCL and FL xenografts. Furthermore, in a patient-derived DLBCL xenograft model, daratumumab anti-tumor activity was comparable to R-CHOP and the addition of daratumumab to either CHOP or R-CHOP led to full tumor regression. In summary, daratumumab constitutes a novel therapeutic opportunity in certain scenarios and these results warrant further clinical development

Advancing manufacture of hiPSC-derived hepatocytes with improved functionality: A nature-inspired protocol

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Harnessing radiotherapy-induced NK-cell activity by combining DNA damage-response inhibition and immune checkpoint blockade.

BackgroundDespite therapeutic gains from immune checkpoint inhibitors (ICI) in many tumor types, new strategies are needed to extend treatment benefits, especially in patients failing to mount effective antitumor T-cell responses. Radiation and drug therapies can profoundly affect the tumor immune microenvironment. Here, we aimed to identify immunotherapies to increase the antitumor response conferred by combined ataxia telangiectasia and Rad3-related kinase inhibition and radiotherapy.MethodsUsing the human papillomavirus (HPV)-negative murine oral squamous cell carcinoma model, MOC2, we assessed the nature of the antitumor response following ataxia telangiectasia and Rad3-related inhibitor (ATRi)/radiotherapy (RT) by performing RNA sequencing and detailed flow cytometry analyses in tumors. The benefit of immunotherapies based on T cell immunoreceptor with Ig and ITIM domains (TIGIT) and Programmed cell death protein 1 (PD-1) immune checkpoint blockade following ATRi/RT treatment was assessed in the MOC2 model and confirmed in another HPV-negative murine oral squamous cell carcinoma model called SCC7. Finally, immune profiling was performed by flow cytometry on blood samples in patients with head and neck squamous cell carcinoma enrolled in the PATRIOT clinical trial of combined ATRi/RT.ResultsATRi enhances radiotherapy-induced inflammation in the tumor microenvironment, with natural killer (NK) cells playing a central role in maximizing treatment efficacy. We demonstrated that antitumor activity of NK cells can be further boosted with ICI targeting TIGIT and PD-1. Analyses of clinical samples from patients receiving ATRi (ceralasertib) confirm the translational potential of our preclinical studies.ConclusionThis work delineates a previously unrecognized role for NK cells in the antitumor immune response to radiotherapy that can be augmented by small-molecule DNA damage-response inhibitors and immune checkpoint blockade

Physical structure of the envelopes of intermediate-mass protostars

Context: Intermediate mass protostars provide a bridge between low- and high-mass protostars. Furthermore, they are an important component of the UV interstellar radiation field. Despite their relevance, little is known about their formation process. Aims: We present a systematic study of the physical structure of five intermediate mass, candidate Class 0 protostars. Our two goals are to shed light on the first phase of intermediate mass star formation and to compare these protostars with low- and high-mass sources. Methods: We derived the dust and gas temperature and density profiles of the sample. We analysed all existing continuum data on each source and modelled the resulting SED with the 1D radiative transfer code DUSTY. The gas temperature was then predicted by means of a modified version of the code CHT96. Results: We found that the density profiles of five out of six studied intermediate mass envelopes are consistent with the predictions of the "inside-out" collapse theory.We compared several physical parameters, like the power law index of the density profile, the size, the mass, the average density, the density at 1000 AU and the density at 10 K of the envelopes of low-, intermediate, and high-mass protostars. When considering these various physical parameters, the transition between the three groups appears smooth, suggesting that the formation processes and triggers do not substantially differ